tbuckley/cabot-search huggingface dataset:
Tunable hybrid hydrogels with multicellular spheroids for modeling desmoplastic pancreatic cancer
Authors: Menekse Ermis, Natashya Falcone, Natan Roberto de Barros, Marvin Mecwan, Reihaneh Haghniaz, Auveen Choroomi, Mahsa Monirizad, Yeji Lee, Jihyeon Song, Hyun-Jong Cho, Yangzhi Zhu, Heemin Kang, Mehmet R. Dokmeci, Ali Khademhosseini, Junmin Lee, Han-Jun Kim
Journal: Bioactive Materials (2023)

The tumor microenvironment consists of diverse, complex etiological factors. The matrix component of pancreatic ductal adenocarcinoma (PDAC) plays an important role not only in physical properties such as tissue rigidity but also in cancer progression and therapeutic responsiveness. Although significant efforts have been made to model desmoplastic PDAC, existing models could not fully recapitulate the etiology to mimic and understand the progression of PDAC. Here, two major components in desmoplastic pancreatic matrices, hyaluronic acid- and gelatin-based hydrogels, are engineered to provide matrices for tumor spheroids composed of PDAC and cancer-associated fibroblasts (CAF). Shape analysis profiles reveals that incorporating CAF contributes to a more compact tissue formation. Higher expression levels of markers associated with proliferation, epithelial to mesenchymal transition, mechanotransduction, and progression are observed for cancer-CAF spheroids cultured in hyper desmoplastic matrix-mimicking hydrogels, while the trend can be observed when those are cultured in desmoplastic matrix-mimicking hydrogels with the presence of transforming growth factor-β1 (TGF-β1). The proposed multicellular pancreatic tumor model, in combination with proper mechanical properties and TGF-β1 supplement, makes strides in developing advanced pancreatic models for resembling and monitoring the progression of pancreatic tumors, which could be potentially applicable for realizing personalized medicine and drug testing applications.
Pharmacokinetics and pharmacogenomics of clozapine in an ancestrally diverse sample: a longitudinal analysis and genome-wide association study using UK clinical monitoring data
Authors: Antonio F Pardiñas, Djenifer B Kappel, Milly Roberts, Francesca Tipple, Lisa M Shitomi-Jones, Adrian King, John Jansen, Marinka Helthuis, Michael J Owen, Michael C O'Donovan, James T R Walters
Journal: The Lancet Psychiatry (2023)

The antipsychotic, clozapine, is the only licensed drug against the treatment-resistant symptoms that affect 20-30% of people with schizophrenia. Clozapine is markedly underprescribed, partly because of concerns about its narrow therapeutic range and adverse drug reaction profile. Both concerns are linked to drug metabolism, which varies across populations globally and is partly genetically determined. Our study aimed to use a cross-ancestry genome-wide association study (GWAS) design to investigate variations in clozapine metabolism within and between genetically inferred ancestral backgrounds, to discover genomic associations to clozapine plasma concentrations, and to assess the effects of pharmacogenomic predictors across different ancestries.
Antisense oligonucleotide targeting DMPK in patients with myotonic dystrophy type 1: a multicentre, randomised, dose-escalation, placebo-controlled, phase 1/2a trial
Authors: Charles A Thornton, Richard Thomas Moxley, Katy Eichinger, Chad Heatwole, Laurence Mignon, W David Arnold, Tetsuo Ashizawa, John W Day, Gersham Dent, Matthew K Tanner, Tina Duong, Ericka P Greene, Laura Herbelin, Nicholas E Johnson, Wendy King, John T Kissel, Doris G Leung, Donovan J Lott, Daniel A Norris, Evan M Pucillo, Wendy Schell, Jeffrey M Statland, Nikia Stinson, Sub H Subramony, Shuting Xia, Kathie M Bishop, C Frank Bennett
Journal: The Lancet Neurology (2023)
Predicting psychotic relapse following randomised discontinuation of paliperidone in individuals with schizophrenia or schizoaffective disorder: an individual participant data analysis
Authors: Lasse Brandt, Kerstin Ritter, Johannes Schneider-Thoma, Spyridon Siafis, Christiane Montag, Hakan Ayrilmaz, Felix Bermpohl, Alkomiet Hasan, Andreas Heinz, Stefan Leucht, Stefan Gutwinski, Heiner Stuke
Journal: The Lancet Psychiatry (2023)
Safety, tolerability, and efficacy of zavegepant 10 mg nasal spray for the acute treatment of migraine in the USA: a phase 3, double-blind, randomised, placebo-controlled multicentre trial
Authors: Richard B Lipton, Robert Croop, David A Stock, Jennifer Madonia, Micaela Forshaw, Meghan Lovegren, Linda Mosher, Vladimir Coric, Peter J Goadsby
Journal: The Lancet Neurology (2023)
Multi-Institutional Randomized Phase II Trial of Gefitinib for Previously Treated Patients With Advanced Non–Small-Cell Lung Cancer
Authors: Masahiro Fukuoka, Seiji Yano, Giuseppe Giaccone, Tomohide Tamura, Kazuhiko Nakagawa, Jean-Yves Douillard, Yutaka Nishiwaki, Johan Vansteenkiste, Shinzoh Kudoh, Danny Rischin, Richard Eek, Takeshi Horai, Kazumasa Noda, Ichiro Takata, Egbert Smit, Steven Averbuch, Angela Macleod, Andrea Feyereislova, Rui-Ping Dong, José Baselga
Journal: Journal of Clinical Oncology (2023)

To evaluate the efficacy and tolerability of two doses of gefitinib (Iressa [ZD1839]; AstraZeneca, Wilmington, DE), a novel epidermal growth factor receptor tyrosine kinase inhibitor, in patients with pretreated advanced non-small-cell lung cancer (NSCLC).
Developmental Consequences of Intimate Partner Violence on Children
Authors: G. Anne Bogat, Alytia A. Levendosky, Kara Cochran
Journal: Annual Review of Clinical Psychology (2023)

Numerous studies associate childhood exposure to intimate partner violence (IPV) with adverse adjustment in the domains of mental health, social, and academic functioning. This review synthesizes this literature and highlights the critical role of child self-regulation in mediating children's adjustment outcomes. We discuss major methodological problems of the field, including failure to consider the effects of prenatal IPV exposure and the limitations of variable-oriented and cross-sectional approaches. Finally, we present a comprehensive theoretical model of the effects of IPV on children's development. This model includes three mechanistic pathways-one that is unique to IPV (maternal representations) and two that are consistent with the effects of other stressors (maternal mental health and physiological functioning). In our model, the effects of these three pathways on child adjustment outcomes are mediated through parenting and child self-regulation. Future research directions and clinical implications are discussed in the context of the model.
Immunologic Effect of Bivalent mRNA Booster in Patients Undergoing Hemodialysis
Authors: Luca Huth, Luise Schäfer, Giovanni Almanzar, Gaia Lupoli, Marie Bischof, Paul R Wratil, Torsten Stövesand, Christiane Drechsler, Oliver T Keppler, Martina Prelog
Journal: New England Journal of Medicine (2023)
Psychoneuroimmunology: An Introduction to Immune-to-Brain Communication and Its Implications for Clinical Psychology
Authors: Julienne E. Bower, Kate R. Kuhlman
Journal: Annual Review of Clinical Psychology (2023)

Research conducted over the past several decades has revolutionized our understanding of the role of the immune system in neural and psychological development and function across the life span. Our goal in this review is to introduce this dynamic area of research to a psychological audience and highlight its relevance for clinical psychology. We begin by introducing the basic physiology of immune-to-brain signaling and the neuroimmune network, focusing on inflammation. Drawing from preclinical and clinical research, we then examine effects of immune activation on key psychological domains, including positive and negative valence systems, social processes, cognition, and arousal (fatigue, sleep), as well as links with psychological disorders (depression, posttraumatic stress disorder, anxiety, schizophrenia). We also consider psychosocial stress as a critical modulator of neuroimmune activity and focus on early life adversity. Finally, we highlight psychosocial and mind–body interventions that influence the immune system and may promote neuroimmune resilience.
Evaluation of BNT162b2 Covid-19 Vaccine in Children Younger than 5 Years of Age
Authors: Flor M Muñoz, Lawrence D Sher, Charu Sabharwal, Alejandra Gurtman, Xia Xu, Nicholas Kitchin, Stephen Lockhart, Robert Riesenberg, Joanna M Sexter, Hanna Czajka, Grant C Paulsen, Yvonne Maldonado, Emmanuel B Walter, Kawsar R Talaat, Janet A Englund, Uzma N Sarwar, Caitlin Hansen, Martha Iwamoto, Chris Webber, Luke Cunliffe, Benita Ukkonen, Silvina N Martínez, Barbara A Pahud, Iona Munjal, Joseph B Domachowske, Kena A Swanson, Hua Ma, Kenneth Koury, Susan Mather, Claire Lu, Jing Zou, Xuping Xie, Pei-Yong Shi, David Cooper, Özlem Türeci, Uğur Şahin, Kathrin U Jansen, William C Gruber
Journal: New England Journal of Medicine (2023)

Safe and effective vaccines against coronavirus disease 2019 (Covid-19) are urgently needed in young children. We conducted a phase 1 dose-finding study and are conducting an ongoing phase 2-3 safety, immunogenicity, and efficacy trial of the BNT162b2 vaccine in healthy children 6 months to 11 years of age. We present results for children 6 months to less than 2 years of age and those 2 to 4 years of age through the data-cutoff dates (April 29, 2022, for safety and immunogenicity and June 17, 2022, for efficacy). In the phase 2-3 trial, participants were randomly assigned (in a 2:1 ratio) to receive two 3-μg doses of BNT162b2 or placebo. On the basis of preliminary immunogenicity results, a third 3-μg dose (≥8 weeks after dose 2) was administered starting in January 2022, which coincided with the emergence of the B.1.1.529 (omicron) variant. Immune responses at 1 month after doses 2 and 3 in children 6 months to less than 2 years of age and those 2 to 4 years of age were immunologically bridged to responses after dose 2 in persons 16 to 25 years of age who received 30 μg of BNT162b2 in the pivotal trial. During the phase 1 dose-finding study, two doses of BNT162b2 were administered 21 days apart to 16 children 6 months to less than 2 years of age (3-μg dose) and 48 children 2 to 4 years of age (3-μg or 10-μg dose). The 3-μg dose level was selected for the phase 2-3 trial; 1178 children 6 months to less than 2 years of age and 1835 children 2 to 4 years of age received BNT162b2, and 598 and 915, respectively, received placebo. Immunobridging success criteria for the geometric mean ratio and seroresponse at 1 month after dose 3 were met in both age groups. BNT162b2 reactogenicity events were mostly mild to moderate, with no grade 4 events. Low, similar incidences of fever were reported after receipt of BNT162b2 (7% among children 6 months to <2 years of age and 5% among those 2 to 4 years of age) and placebo (6 to 7% among children 6 months to <2 years of age and 4 to 5% among those 2 to 4 years of age). The observed overall vaccine efficacy against symptomatic Covid-19 in children 6 months to 4 years of age was 73.2% (95% confidence interval, 43.8 to 87.6) from 7 days after dose 3 (on the basis of 34 cases). A three-dose primary series of 3-μg BNT162b2 was safe, immunogenic, and efficacious in children 6 months to 4 years of age. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04816643.).
G-Quadruplex Structures Are Key Modulators of Somatic Structural Variants in Cancers
Authors: Rongxin Zhang, Huiling Shu, Yuqi Wang, Tiantong Tao, Jing Tu, Cheng Wang, Jean-Louis Mergny, Xiao Sun
Journal: Cancer Research (2023)

G-quadruplexes (G4) are noncanonical secondary genome structures. Aberrant formation of G4s can impair genome integrity. Investigation of the relationship between G4s and somatic structural variants (SV) in cancers could provide a better understanding of the role of G4 formation in cancer development and progression. In this study, we combined bioinformatic approaches and multiomics data to investigate the connection between G4s and the somatic SVs. Somatic SV breakpoints were significantly enriched in G4 regions, regardless of SV subtypes. This enrichment was only observed in regions demonstrated to form G4s in cells ("active quadruplexes"), rather than in regions with a sequence compatible with G4 formation but without confirmed G4 formation ("potential quadruplexes"). Several genomic features affected the connection between G4s and SVs, with the enrichment being notably strengthened at the boundary of topologically associated domains. Somatic breakpoints were also preferentially associated with G4 regions with earlier replication timing and open chromatin status. In patients with cancer with homologous recombination repair defects, G4s and somatic breakpoints were substantially more strongly associated. Machine learning models were constructed that showed that G4 propensity is a potent feature for predicting the density of SV breakpoints. Altogether, these findings suggest that the G4 structures play a critical role in modulating the production of somatic SVs in cancers.G-quadruplex structure formation constitutes a critical step in the production of somatic structural variants in cancers, suggesting G-quadruplex structures as potential targets for future cancer prevention and treatment strategies.
Oral Vancomycin as Secondary Prophylaxis for Prevention of Recurrent <i>Clostridioides difficile</i> Infection
Authors: Leslie L. Chang, Jessica Allegretti, Andrew M. Skinner, Erik R. Dubberke
Journal: New England Journal of Medicine (2023)

This feature about a patient recently treated for C. difficile infection who now needs intravenous antibiotics offers a case vignette accompanied by two essays, one supporting use of oral vancomycin for C. difficile prophylaxis and the other not supporting it.
Case 5-2023: A 67-Year-Old Man with Interstitial Lung Disease, Fever, and Myalgias
Authors: Hemal N. Sampat, Amita Sharma, E. Zachary Nussbaum
Journal: New England Journal of Medicine (2023)

A 67-year-old man with interstitial lung disease presented with fever and myalgias. Laboratory testing revealed pancytopenia and elevated aminotransferase levels. A diagnostic test was performed.
Overcoming Resistance — Omission of Radiotherapy for Low-Risk Breast Cancer
Authors: Alice Y. Ho, Jennifer R. Bellon
Journal: New England Journal of Medicine (2023)

In this issue of the Journal, Kunkler and colleagues1 report the highly anticipated 10-year results of the PRIME II trial, which show that omission of radiotherapy did not affect survival after breast-conserving surgery in women 65 years of age or older with T1 or T2 (tumors ≤3 cm in the largest dimension), node-negative, estrogen receptor (ER)–positive breast cancer. These data offer a response to the long-standing problem of overtreatment in older women with low-risk breast cancer.2 The ability to omit radiotherapy is one of many options in a lengthy list that also includes the use of abbreviated radiotherapy regimens and . . .
Respiratory Syncytial Virus Prefusion F Protein Vaccine in Older Adults
Authors: Alberto Papi, Michael G. Ison, Joanne M. Langley, Dong-Gun Lee, Isabel Leroux-Roels, Federico Martinon-Torres, Tino F. Schwarz, Richard N. van Zyl-Smit, Laura Campora, Nancy Dezutter, Nathalie de Schrevel, Laurence Fissette, Marie-Pierre David, Marie Van der Wielen, Lusine Kostanyan, Veronica Hulstrøm
Journal: New England Journal of Medicine (2023)

Respiratory syncytial virus (RSV) is an important cause of acute respiratory infection, lower respiratory tract disease, clinical complications, and death in older adults. There is currently no licensed vaccine against RSV infection.
Efficacy and Safety of an Ad26.RSV.preF–RSV preF Protein Vaccine in Older Adults
Authors: Ann R. Falsey, Kristi Williams, Efi Gymnopoulou, Stephan Bart, John Ervin, Arangassery R. Bastian, Joris Menten, Els De Paepe, Sjouke Vandenberghe, Eric K.H. Chan, Jerald Sadoff, Macaya Douoguih, Benoit Callendret, Christy A. Comeaux, Esther Heijnen
Journal: New England Journal of Medicine (2023)

Respiratory syncytial virus (RSV) can cause serious lower respiratory tract disease in older adults, but no licensed RSV vaccine currently exists. An adenovirus serotype 26 RSV vector encoding a prefusion F (preF) protein (Ad26.RSV.preF) in combination with RSV preF protein was previously shown to elicit humoral and cellular immunogenicity.
Breast-Conserving Surgery with or without Irradiation in Early Breast Cancer
Authors: Ian H. Kunkler, Linda J. Williams, Wilma J.L. Jack, David A. Cameron, J. Michael Dixon
Journal: New England Journal of Medicine (2023)

Limited level 1 evidence is available on the omission of radiotherapy after breast-conserving surgery in older women with hormone receptor-positive early breast cancer receiving adjuvant endocrine therapy.We performed a phase 3 randomized trial of the omission of irradiation; the trial population included women 65 years of age or older who had hormone receptor-positive, node-negative, T1 or T2 primary breast cancer (with tumors ≤3 cm in the largest dimension) treated with breast-conserving surgery with clear excision margins and adjuvant endocrine therapy. Patients were randomly assigned to receive whole-breast irradiation (40 to 50 Gy) or no irradiation. The primary end point was local breast cancer recurrence. Regional recurrence, breast cancer-specific survival, distant recurrence as the first event, and overall survival were also assessed.A total of 1326 women were enrolled; 658 were randomly assigned to receive whole-breast irradiation and 668 to receive no irradiation. The median follow-up was 9.1 years. The cumulative incidence of local breast cancer recurrence within 10 years was 9.5% (95% confidence interval [CI], 6.8 to 12.3) in the no-radiotherapy group and 0.9% (95% CI, 0.1 to 1.7) in the radiotherapy group (hazard ratio, 10.4; 95% CI, 4.1 to 26.1; P<0.001). Although local recurrence was more common in the group that did not receive radiotherapy, the 10-year incidence of distant recurrence as the first event was not higher in the no-radiotherapy group than in the radiotherapy group, at 1.6% (95% CI, 0.4 to 2.8) and 3.0% (95% CI, 1.4 to 4.5), respectively. Overall survival at 10 years was almost identical in the two groups, at 80.8% (95% CI, 77.2 to 84.3) with no radiotherapy and 80.7% (95% CI, 76.9 to 84.3) with radiotherapy. The incidence of regional recurrence and breast cancer-specific survival also did not differ substantially between the two groups.Omission of radiotherapy was associated with an increased incidence of local recurrence but had no detrimental effect on distant recurrence as the first event or overall survival among women 65 years of age or older with low-risk, hormone receptor-positive early breast cancer. (Funded by the Chief Scientist Office of the Scottish Government and the Breast Cancer Institute, Western General Hospital, Edinburgh; ISRCTN number, ISRCTN95889329.).
Patient-Reported Symptom Complexity and Acute Care Utilization Among Patients With Cancer: A Population-Based Study Using a Novel Symptom Complexity Algorithm and Observational Data
Authors: Linda Watson, Siwei Qi, Claire Link, Andrea DeIure, Arfan Afzal, Lisa Barbera
Journal: Journal of the National Comprehensive Cancer Network (2023)

Patients with cancer in Canada are often effectively managed in ambulatory settings; however, patients with unmanaged or complex symptoms may turn to the emergency department (ED) for additional support. These unplanned visits can be costly to the healthcare system and distressing for patients. This study used a novel patient-reported outcomes (PROs)-derived symptom complexity algorithm to understand characteristics of patients who use acute care, which may help clinicians identify patients who would benefit from additional support.This retrospective observational cohort study used population-based linked administrative healthcare data. All patients with cancer in Alberta, Canada, who completed at least one PRO symptom-reporting questionnaire between October 1, 2019, and April 1, 2020, were included. The algorithm used ratings of 9 symptoms to assign a complexity score of low, medium, or high. Multivariable binary logistic regressions were used to evaluate factors associated with a higher likelihood of having an ED visit or hospital admission (HA) within 7 days of completing a PRO questionnaire.Of the 29,133 patients in the cohort, 738 had an ED visit and 452 had an HA within 7 days of completing the PRO questionnaire. Patients with high symptom complexity had significantly higher odds of having an ED visit (OR, 3.10; 95% CI, 2.59-3.70) or HA (OR, 4.20; 95% CI, 3.36-5.26) compared with low complexity patients, controlling for demographic covariates.Given that patients with higher symptom complexity scores were more likely to use acute care, clinicians should monitor these more complex patients closely, because they may benefit from additional support or symptom management in ambulatory settings. A symptom complexity algorithm can help clinicians easily identify patients who may require additional support. Using an algorithm to guide care can enhance patient experiences, while reducing use of acute care services and the accompanying cost and burden.
Patient-Reported Outcome Measures in Chemotherapy-Induced Peripheral Neurotoxicity: Defining Minimal and Clinically Important Changes
Authors: Tiffany Li, Hannah C. Timmins, Terry Trinh, David Mizrahi, Michelle Harrison, Lisa G. Horvath, Peter Grimison, Michael Friedlander, Matthew C. Kiernan, Madeleine T. King, Claudia Rutherford, David Goldstein, Susanna B. Park
Journal: Journal of the National Comprehensive Cancer Network (2023)

Background: Chemotherapy-induced peripheral neurotoxicity (CIPN) is a common complication of cancer treatment that produces functional disability. Increasingly, patient-reported outcome measures (PROMs) are used to assess CIPN, providing a broader symptom perspective than clinician-graded scales. Understanding when a reported change in CIPN symptoms meets the threshold for clinical significance is challenging. This study aimed to provide interpretation guidelines for validated CIPN PROMs, and thereby enable estimation of thresholds to identify clinically relevant symptoms. Methods: Patients commencing neurotoxic cancer treatments were assessed at 3 timepoints: baseline, midtreatment, and end-of-treatment. Trajectory of CIPN development was assessed by means of CIPN PROMs, EORTC Quality of Life – Chemotherapy-Induced Peripheral Neuropathy questionnaire (QLQ-CIPN20), and Functional Assessment of Cancer Therapy/Gynecologic Oncology Group – Neurotoxicity questionnaire (FACT/GOG-NTX). Thresholds were estimated for CIPN PROMs using the NCI CTCAE sensory neuropathy scale as the clinical anchor by midtreatment and end-of-treatment. Patients were assigned to a clinical change group according to CIPN development: either no development; grade 1 neuropathy (minimally important difference [MID]); or grade 2 neuropathy (clinically important difference). Distribution-based estimates (SD, 0.5) were also evaluated as supportive evidence. Results: In total, 406 patients were recruited to the study, of whom 62% (n=199/320) developed CIPN by midtreatment and 80% (n=274/343) by end-of-treatment. Anchor-based MID estimates by midtreatment were 5.06 (95% CI, 4.26–5.86) for the QLQ-CIPN20 and 3.54 (95% CI, 2.87–4.20) for the FACT/GOG-NTX. End-of-treatment MIDs were estimated to be 7.32 (95% CI, 6.23–8.40) for the QLQ-CIPN20 and 4.84 (95% CI, 3.98–5.70) for the FACT/GOG-NTX. Distribution-based MID estimations yielded lower values than anchor-based methods, at 3.73 for the QLQ-CIPN20 and 2.64 for the FACT/GOG-NTX at midtreatment and 5.52 for the QLQ-CIPN20 and 3.64 for the FACT/GOG-NTX at end-of-treatment. Conclusions: Findings from the present series aid meaningful interpretation for commonly used validated CIPN PROMs and provide thresholds that serve as guidance on how to interpret score changes, which will be useful for design and evaluation of clinical trials and clinical practice.